Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6]P(=O)(OCC)OCC)#[N:4].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1C=O.O>O1CCCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:6]=[CH:5][C:3]#[N:4]
Reactant: O=Cc1ccccn1
Reactant: CCOP(=O)(CCC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC=Cc1ccccn1
Reaction time: 1 h
Yield: 15.4 %

Procedure:
Sodium hydride (ca. 60%, 1.0 g, 28.1 mmol) was suspended in tetrahydrofuran (12 ml), and a solution of diethyl cyanoethylphosphonate (4.7 g, 26.8 mmol) in tetrahydrofuran (12 ml) was added thereto under ice cooling condition. The reaction mixture was stirred for 1 hr. A solution of 2-pyridinecarbaldehyde (2.7 g, 25.0 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at 0° C. to room temperature for 6 hrs. The reaction mixture was combined with water under ice cooling condition, concentrated to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (100 g) column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give Z-form of the titled compound (0.50 g, 15%). And simultaneously, the fractions eluted with hexane-ethyl acetate (3:2, v/v) were collected and concentrated to give E-form of the titled compound.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([OH:28])[CH2:8]OS(C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)(=O)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]2[N:34]=[CH:35][NH:36][C:32]=2[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:6][C@H:7]([OH:28])[CH2:8][N:34]2[C:33]3[CH:37]=[C:38]([Cl:39])[C:30]([Cl:29])=[CH:31][C:32]=3[N:36]=[CH:35]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)OC[C@@H](O)CC2CCCC2)c(C(C)C)c1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O[C@@H](CC1CCCC1)Cn1cnc2cc(Cl)c(Cl)cc21
Temperature: 160 °C
Yield: 39.3 %

Procedure:
Two large (2-5 mL) microwave reactor tubes were charged with (S)-2,4,6-Triisopropyl-benzenesulfonic acid 3-cyclopentyl-2-hydroxy-propyl ester (Example 6, Step A, 1.88 g, 4.6 mmol), 5,6-dichlorobenzimidazole (859 mg, 4.6 mmol), K2CO3 (1.27 g, 9.2 mmol) and DMF (4 mL). The tubes were then heated to 160° C. for 6 minutes. The reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted a total of 2 times with ethyl acetate and the combined organics were dried over MgSO4. The solvent was removed and the resulting oil was chromatographed over silica gel using a linear gradient of 0-100% ethyl acetate in hexane to afford 566 mg (40%) of the title compound as a solid: HPLC-MS calcd. for C15H18Cl2N2O (M+H+) 313.1, found 313.2.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:23]=[CH:24][C:25]3[N:31]4[N:32]=[N:33][N:34]=[C:30]4[CH2:29][S:28][CH:27]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=4)[C:26]=3[CH:42]=2)=[O:21])=[CH:16][CH:15]=1.CCOC(C)=O>C(OCC)C.C1COCC1>[Cl:41][C:37]1[CH:36]=[C:35]([CH:27]2[C:26]3[CH:42]=[C:22]([C:20]([C:17]4[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=4)([C:7]4[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=4)[OH:21])[CH:23]=[CH:24][C:25]=3[N:31]3[N:32]=[N:33][N:34]=[C:30]3[CH2:29][S:28]2)[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCc1nnnn1-2
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1cccnc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCc1nnnn1-2
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 6.3 %

Procedure:
nBuLi (0.009 mol) was added dropwise at −70° C. to a mixture of 3-bromo-pyridine (0.009 mol) in diethyl ether (10 ml) under N2 flow. The mixture was stirred at −70° C. for 15 minutes. A suspension of intermediate (31) (0.003 mol) in THF (30 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour, then brought slowly to room temperature, stirred overnight and poured out into ice water. EtOAc was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.12 g (7%). This fraction was taken up in diethyl ether. The precipitate was filtered off and dried in a vacuum, yielding 0.1 g (6%) of 6-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(3-pyridinyl)-4H,6H-tetrazolo[1,5-a][4,1]benzothiazepine-8-methanol, MS (MH+) m/e: 532, 534, 536.
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+].CN(C)C=O.S([O:30][CH2:31][C:32]1([CH2:36][CH3:37])[CH2:35][O:34][CH2:33]1)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.O>[CH2:36]([C:32]1([CH2:31][O:30][C:11]2[CH:12]=[CH:2][C:3]([C:4]([OH:6])=[O:5])=[CH:9][CH:10]=2)[CH2:35][O:34][CH2:33]1)[CH3:37]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(COc2ccc(C(=O)O)cc2)COC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
50 g of ethyl hydroxybenzoate and 21 g of potassium hydroxide were added to 400 ml of dimethylformamide, and stirred at 70° C. for 1 hour. This was cooled to 45° C., and 100 g of 3-[(tosyloxy)methyl]-3-ethyloxetane was dropwise added to it. Kept at 45° C., this was stirred for 3 hours. Water and toluene were added to it for liquid-liquid separation. The toluene layer was washed with 3% hydrochloric acid, saturated sodium hydrogencarbonate and water, and then toluene was evaporated away. To the resulting residue, added were 50 g of sodium hydroxide, 500 ml of ethanol and 200 ml of water, and this was refluxed for 2 hours. Ethanol was evaporated away, and the resulting residue was poured into 500 ml of 5% hydrochloric acid, and a crystal was thus formed. The crystal taken out through filtration was recrystallized from a mixed solvent of ethanol and water, and 60 g of 4-(3-ethyloxetan-3-ylmethoxy)benzoic acid (OX5) was obtained. Its melting point was 127.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:14]([NH:15][NH2:16])=[CH:13][C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:14]3[NH:15][N:16]=[C:22]([NH:23][CH3:24])[C:13]=3[C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:20][CH:21]=1
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccc(Br)cc2)c1=O
Reactant: CN=C=S
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(Br)cc2)c1=O
Yield: 47 %

Procedure:
A solution of 1-(4-bromobenzyl)-6-hydrazino-3-propyluracil (4.15 g, 11.8 mM) and methyl isothiocyanate (2.7 ml, 40 mM) in DMF (50 ml) was heated at 120° C. for 24 hours. To the reaction solution was added 50% methanol (15 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol gave colorless needles (2.19 g, 47%), m.p. 308°-310° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[Cl:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: Nc1ccccc1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccccc1Cl
Yield: 45.2 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol) and 2-chloroaniline (1.6 ml, 15 mmol) in dioxan (10 ml) were heated at reflux for 30 minutes, then allowed to cool. The product was filtered off, converted to free base, and recrystallised from methanol to give 3-butyryl-4-(2-chlorophenylamino)-8-methylquinoline (1.53 g), m.p. 130°-131°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:18]=[C:19]([NH:22][C:23](=O)OC(C)(C)C)[S:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.[H-].[Na+].BrC[CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(Cl)Cl>[CH:35]1([CH2:34][CH2:23][NH:22][C:19]2[S:20][CH:21]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:18]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: BrCCC1CCCCC1
Reactant: Cn1nnnc1C(=NOCc1csc(NC(=O)OC(C)(C)C)n1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nnnc1C(=NOCc1csc(NCCC2CCCCC2)n1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A stirred solution of tert-butyl {4-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}carbamate (0.185 g, 0.445 mmol, 1 eq.) in 3 ml of dry DMF was treated with NaH (60% dispn in mineral oil, 0.019 g, 0.49 mmol, 1.1 eq.) added in one portion. After 20 mins (2-bromoethyl)cyclohexane (0.096 g, 0.49 mmol, 1.1 eq.) was added and the reaction was stirred for 1 hr. Then TFA (1.48 g, 12.98 mmol, 30 eq.) was added carefully and the reaction was heated to 60° C. for 12 h. After cooling, sat. aqueous Na2CO3 was added followed by DCM. The layers were separated and the aqueous layer was extracted with DCM. The organics were combined, washed with sat. aqueous Na2CO3, dried over MgSO4 and concentrated. The crude was purified by chromatography on silica gel to give N-(2-cyclohexylethyl)-4-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-amine (0.144 g, 76% yield) as a clear viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:7]2[C:12]([C:13]=1[CH:14]=[O:15])=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[CH:8]=2)=[O:4].CC(=CC)C.[O-:30]Cl=O.[Na+]>CC(O)(C)C.O1CCOCC1.O>[CH3:17][O:16][C:9]1[CH:8]=[C:7]2[C:12]([C:13]([C:14]([OH:30])=[O:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1c(C=O)c2ccc(OC)cc2n1Cc1ccccn1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(C(=O)O)c2ccc(OC)cc2n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
General Procedure K. To a suspension of methyl3-formyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 91, 1.64 g, 5.07 mmol) in t-BuOH (120 ml) and dioxane (20 ml) was added 2-methyl-2-butene (25 ml) and a solution of NaH2PO4 (7.3 g, 61 mmol) and NaClO2 (80%, 5.7 g, 50.7 mmol) in H2O (100 ml). The reaction was stirred at room temperature for 6 h, extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[C:14]([CH3:19])[C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([Mg]Br)[CH:22]([CH3:24])[CH3:23]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([OH:18])[CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([CH3:19])[C:13]=2[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C=O)oc2ccc(OCc3ccccc3)cc12
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: Cc1c(C(O)CC(C)C)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
To a solution (15 mL) of 5-(benzyloxy)-3-methyl-1-benzofuran-2-carbaldehyde (1.2 g) synthesized in the above-mentioned (3) in tetrahydrofuran was added dropwise isobutylmagnesium bromide (1M, tetrahydrofuran solution) under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 15 min, and aqueous ammonium chloride solution was added to quench the reaction. The reaction mixture was extracted with ethyl acetate, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give 1-[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl]-3-methylbutan-1-ol (0.82 g, 56%) as a pale-yellow oil. This was dissolved in tetrahydrofuran (15 mL), and thionyl chloride (0.35 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min then ice-cooled, and saturated aqueous sodium hydrogen carbonate solution (15 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylacetamide (15 mL), sodium iodide (0.56 g), sodium carbonate (0.38 g) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.63 g) synthesized in Example 2(2) were added to the solution, and the mixture was stirred at 80° C. for 12 hr. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (0.46 g, 33%) as a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:7])=[O:3].[NH2:17][NH2:18]>C(Cl)Cl>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]([CH3:7])[CH2:5][O:4][C:2]([NH:17][NH2:18])=[O:3])([O-:16])=[O:15]
Reactant: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Reactant: NN
Solvent: ClCCl
Product: CC(COC(=O)NN)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
A solution of 2-(2-nitrophenyl)propyl chloroformate (6.0 g, 24.6 mmol) in methylene chloride (20 mL) was added dropwise to a solution of hydrazine (3.0 mL, 98 mmol) in methylene chloride (50 mL) over a period of 30 min. The reaction mixture was stirred at room temperature for an additional 15 min. The solvent was evaporated to afford light brown oil. The residue was purified on a silica gel column. Elution of the column with 20% ethyl acetate in hexanes gave 3.35 g (14 mmol, 57% yield) of 2-(2-nitrophenyl)propoxycarbonyl hydrazine. 1H-NMR (600 MHz, DMSO-d6): δ 8.10 (s, 2H, CONH), 7.82 (d, J=7.5 Hz, 1 H, Ar—H), 7.67 (m, 2 H, Ar—H), 7.47 (m, 1 H, Ar—H), 4.15 (d, J=7.2 Hz, 2 H, CH2), 3.9 (s, 2 H, NH2), 3.39 (m, 1 H, CH), 1.25 (d, J=6.9 Hz, 3 H, CH3). 13C-NMR (150 MHz, DMSOd6): δ 157.99 (OCOR), 150.00 (C ipso to NO2), 136.72 (C ipso to CH(CH3)CH2OCOR), 132.86 (C para to NO2), 128.55 (C para to CH(CH3)CH2OCOR), 127.69 (C ortho to CH(CH3)CH2OCOR), 123.68 (C ortho to NO2), 67.49 (CH2OCOR), 33.36 (CH), 17.93 (CH3). Mass analysis (MALDI-TOF): calculated for C10H13N3O4 239.23, found 239.20 (C10H13N3O4Na 262.18 is the major peak). TLC: 5% methanol in chloroform, Rf=0.5.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[C:37]([NH:56][CH2:57][CH2:58][NH:59][CH2:60][CH2:61][NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:59]([CH2:60][CH2:61][NH:62][C:63](=[O:69])[O:64][C:65]([CH3:66])([CH3:68])[CH3:67])[CH2:58][CH2:57][NH:56][C:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)NCCNCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1ncc(NC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 92.9 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)pyrazol-4-yl]carbamate (712 mg) and tert-butyl 2-{[2-(tritylamino)ethyl]amino}ethylcarbamate (668 mg) in dehydrated chloroform (4 ml) was added N-ethyldiisopropylamine (0.257 ml), and the mixture was stirred under reflux for 16 hours. To the reaction mixture was added ethyl acetate, and the solution was washed successively with water, 5% aqueous citric acid solution, 1M aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% methanol/methylene chloride to give tert-butyl (2-{N-({[1-methyl-5-(tritylamino)pyrazol-4-yl]amino}carbonyl)-N-[2-(tritylamino)ethyl]amino}ethyl)carbamate (1.15 g) as a solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])(=O)[CH3:2].[BH4-].[Na+].[C:16](O)(=O)C.O>O1CCCC1>[CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:16])=[O:11])[CH3:2]
Reactant: CC(=O)O
Reactant: COC(=O)CCCCCNC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCNCCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude methyl 6-acetylamino-hexanoate (5.19 g) is dissolved in tetrahydrofuran (50 ml) and thereto is added sodium borohydride (5.03 g). The reaction solution is heated under reflux and thereto is added dropwise acetic acid (7.6 ml) and the mixture is heated under reflux for 1 hour and 30 minutes. To the reaction solution is added water under ice-cooling and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in ethanol (30 ml) and thereto is added a 4N-hydrochloric acid in ethyl acetate (7.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution are added a 2N-aqueous sodium hydroxide solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give ethyl 6-ethylamino-hexanoate (1.74 g) as a crude product. MS (m/z): 188 [M+H]+
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:17]=[N:18][N:19](C)[N:20]=3)[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:22][CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.[CH3:44]O>[Pd]>[NH3:8].[F:37][C:34]([F:35])([F:36])[C:26]1[CH:25]=[C:24]([CH2:23][O:22][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:15][C@H:14]3[C:16]2[N:20]([CH3:44])[N:19]=[N:18][N:17]=2)[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=1
Reactant: Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Reactant: CO
Agent: [Pd]
Product: Cn1nnnc1[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: N
Reaction time: 2 h
Yield: 58 %

Procedure:
Palladium on carbon (10%) 100 mg was added to a solution of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(1-methyl-1H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 139a; 170 mg, 0.3 mmol) in methanol (10 ml). The mixture was transferred to the Parr™ apparatus and hydrogenated at 45 psi. for 2 hours. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluting with 180:8:1 dichloromethane:methanol:ammonia to yield the title compound (84 mg, 58%). The hydrochloride salt was prepared by treatment with ethereal HCl.
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[CH:28]1([NH:34][CH:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([N:34]([C@H:35]2[CH2:36][CH2:37][C@H:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:39][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: c1ccc(C2CCC(NC3CCCCC3)CC2)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](c3ccccc3)CC2)s1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Example 38) via cyclohexyl-(4-phenyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:33])/[CH:5]=[C:6](/[CH:8]=[CH:9]/[C@@H:10]1[CH2:12][C@@:11]1([C:14]1[CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:17]2[O:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]=2[CH:24]=1)[CH3:13])\[CH3:7])C.C(O)C.[OH-].[Na+].O>C(#N)C>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:16]2[C:17]3[O:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]=3[CH:24]=[C:14]([C@@:11]3([CH3:13])[CH2:12][C@H:10]3/[CH:9]=[CH:8]/[C:6](/[CH3:7])=[CH:5]/[C:4]([OH:33])=[O:3])[CH:15]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@@H]1C[C@]1(C)c1cc(-c2ccc(OC)cc2)c2c(c1)C(C)(C)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2cc([C@@]3(C)C[C@H]3/C=C/C(C)=C/C(=O)O)cc3c2OCC3(C)C)cc1

Procedure:
Following General Procedure H and using (E)-3-((E)-2-{(1S, 2S)-2-[7-(4-methoxy-phenyl)-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl]-2-methyl-cyclopropyl}-vinyl)-but-2-enoic acid ethyl ester (Compound 31, 0.041 g, 0.09 mmol), ethanol (5 mL), and 5M aqueous sodium hydroxide followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained (0.026 g, 65%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=4)[CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([CH3:27])[CH3:26]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N:31]5[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]5)[CH:20]=4)[CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc2cc(Br)ccc2c1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(c2ccc3cc(C(=O)Nc4ccc5cccnc5c4)ccc3c2)CC1

Procedure:
This material was prepared analogous to the procedure described for Example 33. 6-Bromo-naphthalene-2-carboxylic acid quinolin-7-ylamide, Example 32(b), (116 mg, 0.31 mmol) reacted with 1-isopropylpiperazine (315 mg, 2.46 mmol, Aldrich) to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 426 (M+1).